If more funding and research would be dedicated to understanding what is contained in the document that follows, I believe that a cure for practically every neurological disease would be found. This document is found at the Paroxysmal Dyskinesia website. This is not light reading.michael


Neurotransmitter Systems, Pharmacology, and Anatomy

"The basal ganglia are undoubtedly among the most complex and least understood structures in the mammalian forebrain and, as in the case of the cerebral cortex, to which they are functionally and anatomically related, they have been associated with the widest range of possible functions."

Although an understanding of the form and function of the basal ganglia to a large extent remains elusive, the assumption that they facilitate initiation of willed movements is generally accepted. Many studies further suggest that the effects of the basal ganglia are widespread, in particular playing a key role in organizing goal-directed behaviors such as complex thought and reasoning. Before one can fully explore the proposed capabilities of the basal ganglia, however, one must have a grasp on their less nebulous elements. Transmission of information in the basal ganglia, like every other organ in the central nervous system, depends upon the functions of neurotransmitters. Thus, a foundation in neurotransmitters, the basic mediator of the transfer of information between neurons, is essential to an understanding of the circuits of the basal ganglia.

Neurotransmitter SystemsTo qualify as a neurotransmitter, a candidate chemical must be released into the synaptic cleft by a presynaptic neuron and communicate with a post synaptic counterpart. More specifically, a neurotransmitter is synthesized and stored in the presynaptic neuron, released by the presynaptic axon terminal upon stimulation, and produces a response in the post-synaptic cell that mimics the response produced by the neurotransmitter from the presynaptic neuron. When the neurotransmitter has completed its function, a mechanism terminates the transmitter's action and there is a pharmacologically relevant response at a defined postsynaptic receptor.

Most of the known neurotransmitter molecules are either amino acids, amines which are derived from amino acids, or peptides, constructed from amino acids. Amino acids and amines are synthesized by enzymes in the cytosol of the cell and then loaded into the synaptic vesicles in the axon terminal. The process for peptides, which are larger molecules, begins in the rough endoplasmic reticulum (rough ER) when a precursor peptide is synthesized. This molecule is cleaved in the Golgi apparatus where secretory vesicles containing the peptide bud off from the apparatus and transport the granules down the axon to the terminal. Beyond composition, the difference in synthesis is the clearest way to differentiate amines and amino acids from their peptide counterparts.

Amines and amino acids have a unique identity with respect to a neuron, and therefore may be used to differentiate neurons into distinct classes. In contrast, neurons containing peptides usually release an amino acid or amine in addition to a peptide. Neurotransmitter release, regardless of whether it's an amine, amino acid, or peptide, is triggered by the arrival of an action potential in the axon terminal. This impulse causes a depolarization of the terminal membrane triggering voltage-gated calcium channels to open. The inwardly directed concentration gradient of calcium results in a flooding of the axon terminal as long as the calcium channels are open. The influx of calcium, triggers neurotransmitter release from the synaptic vesicles through exocytosis. Once the neurotransmitter is released into the synaptic cleft it can produce a variety of postsynaptic effects, depending upon the nature of the receptors on the postsynaptic neuron.

There are two general categories of neurotransmitter receptors: ligand-gated ion channels, which are membrane spanning proteins consisting of five subunits with a pore between them, and G-protein-coupled receptors, either ion channels or enzymes that generate intracellular second messengers. A ligand is a category of substances that bind to receptors, including, but not limited to, transmitters. Amines and amino acid neurotransmitters mediate both excitatory and inhibitory fast chemical synaptic transmission by acting on ligand-gated channels. When a neurotransmitter binds to a ligand-gated ion channel, the normally closed pore experiences a conformational change allowing ions to pass through the pore.

G-protein receptors function through a more complicated process. The name of the receptor comes from the type of protein that serves as the intermediary in activating intracellular responses in the postsynaptic element. Although there are at least twelve different kinds of G proteins, the general form consists of separate alpha, beta and gamma subunits. When a ligand binds to a G protein-coupled receptor, there is a conformational change in the receptor increasing its affinity for the G protein. The subunit releases GDP, which is converted to GTP, and binds to the alpha subunit. The newly formed G-alpha subunit is free to move along the intracellular face of the postsynaptic membrane and activate an effector protein.

There are two general forms of effector proteins: G-protein-gated ion channels in the membrane and enzymes that synthesize molecules called second messengers which in turn diffuse away in the cytosol. Within this system, the same neurotransmitter can have different actions depending upon which effector it activates. Each receptor, in turn, triggers varied intracellular responses, usually via enzymes which regulate phosphorylization in cellular proteins. The G-alpha subunit eventually terminates its own activity by converting the bound GTP to GDP allowing the G-alpha and G-beta-gamma subunits to reunite and thus returning the G-protein to its initial state.

Certain neurons contain receptors known as autoreceptors, which allow neurotransmitters to act upon the presynaptic axon terminal. The consequences of activation of these receptors vary and is not fully understood. That said, two known effects are inhibition of neurotransmitter release and, less frequently, accelerated neurotransmitter synthesis. Autoreceptors are typically G-protein-coupled receptors that stimulate second messenger formation. In pharmacological tests it has been noted that very low dosages of drugs are effective in disorders involved with autoreceptors. Consequently, it is believed that an important function of autoreceptors is maintaining balance of neurotransmitters in the synaptic cleft by acting as a safety valve when the concentration is either too high or low.

The general neurotransmitter cycle is completed through the recovery and/or degradation of the molecule. After interacting with postsynaptic receptors, the neurotransmitter must be cleared from the synaptic cleft in order for another round of transmission to occur. If the neurotransmitter remains in the cleft for too long a state of desensitization follows where transmission cannot occur. The neuron prevents such a state through a variety of removal techniques. Diffusion of transmitter molecules away from the synapse is the simplest form; however, for most amines and amino acid transmitters this is aided by reuptake of the neurotransmitter into the presynaptic axon terminal. A neurotransmitter may be enzymatically destroyed in the synaptic cleft or in the terminal. Other neurotransmitters are transported to the terminal and instead of being destroyed are reloaded into synaptic vesicles. The end result is that the synaptic cleft is free of used neurotransmitters.

Although all synaptic transmission follows the general pattern of synthesis of the neurotransmitter in the presynaptic neuron, its release into the synaptic cleft, and finally the elicitation of a response in the post synaptic neuron, the actual mechanics varies between molecules. One way to differentiate neurotransmitters is through their biochemical structure. Four important groups are the cholinergic, catecholaminergic, serotonergic, and amino acidergic groups. Cholinergic neurons release, acetylcholine (ACh,) a neurotransmitter involved in neurosmuscular transmission, the autonomic nervous system, learning and memory, sleep, and arousal.

Synthesis of the molecule requires the enzyme choline acetyltransferase (ChAt). An enzyme only found within cholinergic neurons, it serves as a marker for the group. ChAt has been localized to cell bodies in the basal forebrain, interneurons in the striatum, the autonomic ganglia, and in the spinal cord, implying that acetylcholine is used at these sites. ACh is formed when ChAt transfers an acetyl group from acetyl CoA to choline. Transmission is mediated through both ligand-gated, with nicatinic receptors, and G-protein-gated channels, using muscarinic receptors. Nicotinic receptors are most prevalent at the neuromuscular junction. Agonists, such as its namesake nicotine, reduce muscle contraction. The muscarinic receptor is also named after an agonist, muscarine, which affects the heart. The agent which degrades ACh, acetylchoinesterase (AChE) into choline and acetic acid can be inactivated or retarded to produce the results of poisons such as nerve gasses.

Like ACh, catecholaminergic neurons are also involved with the regulation of movement, as well as mood, attention, and visceral function. There are three types of catecholaminergic neurons: dopaminergic, adrenergic, and noradrenergic. These three neurotransmitters all share the same precursor, tyrosine, a chemical group called a catechol. The first step in the synthesis of any catecholaminergic neurotransmitter, the conversion of tyrosine to the compound dopa, is catalyzed by tyrosine hydroxylase (TH.) This enzyme serves as a marker and is rate limiting for all catecholaminergic neurons.

Dopa is converted into the neurotransmitter dopamine through the actions of the enzyme dopa decarboxylase. A respected model explains the regulation of the distribution, storage, and release of dopamine through the pre-synaptic autoreceptors D2 and alpha2. The amount of transmitter released by the neuron is regulated by negative feedback through the pre-synaptic receptors. When an excess of dopamine accumulates in the cleft, autoreceptors inhibit tyrosine hydroxase causing a decrease in the production of dopamine. The agents released from the neuron can act both upon the terminal in which they originate as well as on the post-synaptic element. Although dopaminergic neurons are one of a limited group of sites in which autoreceptors have been proven to exist through in vitro and in vivo studies, it is suggested that receptors on the presynaptic element are widespread throughout neurotransmitter systems.

Dopamine is converted into norepinepherine(NE) in the synaptic vesicles through the action of dopamine-beta-hydroxylase. NE is further transformed to the third of the catecholamine neurotransmitters, epinephrine, in the cytosol of the axon terminal. Adrenergic neurons contain the enzyme phentolamine N-methltransferase(PNMT) which converts NE to epinephrine. All three of the catecholamines utilize G-protein-coupled receptors. In addition to its autoreceptors, dopamine uses a host of receptors which activate or inhibit adenyl cyclase. Receptors used by NE and epinephrine utilize phospholipase C as well as adenyl cyclase. For example, the binding of NE to the beta receptor activates the stimulatory G-protein, Gs, which in turn stimulates the membrane-bound enzyme adenyl cyclase. This enzyme converts ATP to cyclic AMP. The change in the concentration of cAMP in the cytosol triggers protein kinase A (PKA) a specific downstream enzyme. PKA phosphorylates the cell's voltage-gated calcium channels, increasing their activity. Activation of another type of NE receptor, the alpha2, excites the inhibitory G-protein(Gi) which effectively suppresses the activity of adenyl cyclase and the stimulatory system in general. Finally, the actions of catecholamines in the synaptic cleft are terminated by selective reuptake into the axon terminal where they are either inactivated by the enzymes monoamine oxidase or catechol-O-methyl transferase or reloaded into synaptic vesicles for reuse. As in the case of acetylcholine, receptor responses can be regulated through treatment with agonists and uptake inhibitors, as well as MAO inhibitors.

The synthesis of the neurotransmitter serotonin, (5-HT) involved in mood, arousal, aggression, eating behavior, and hormonal secretion, also occurs in two steps. First the enzyme tryptophan hydroxylase converts tryptophan into 5-HTP which the enzyme 5-HTP decarboxylase converts into 5-HT. Serotonin is inactivated, like epinephrine, by the enzyme monoamine oxidase as well as by reuptake into cells by a 5-HT transporter.

The amino acidergic group of neurotransmitters includes glycine (Gly), glutamate (Glu) as well as gamma-aminobutyric acid (GABA). Glutamate and glycine, excitatory amino acids derived from the Krebs cycle, function in learning, memory, and cognitive functions. Glutamate is abundant in the CNS and can be found in almost every cortical region. GABA, involved in fast inhibitory neurotransmission, is synthesized from glutamate by the enzyme glutamic acid decarboxylase. (GAD) Consequently, this enzyme serves as a good marker for GABAegic neurons. In contrast to glutamate and glycine, GABA is not one of the twenty amino acids that make up proteins. Instead, GABA is synthesized only by those neurons that use it as a neurotransmitter. Amino acids mediate most of the fast synaptic transmission in the CNS through ligand-gated channels.

Glutamate acts on three forms of receptors, all taking the names of their most potent selective chemical agonists: AMPA, NMDA, and kainate. Most glutamate mediated excitatory transmission has components contributed by both AMDA and NMDA gated channels since they often coexist on the same cells. While both NMDA and AMPA-gated channels cause excitation of a cell by admitting sodium, NMDA-gated channels are also permeable to calcium and inward ionic current. GABA and glycine mediate the majority of synaptic inhibition in the CNS through gating a chlorine channel. The synaptic actions of glycine, glutamate, or GABA are terminated by selective uptake into the presynaptic terminal. GABA is then metabolized by the enzyme GABA transaminase.

The Basal GangliaThe basal ganglia are the site of a wealth of neurotransmitter diversity. According to Ann M. Grabiel, of the Massachusetts Institute of Technology, "the basal ganglia have been found to contain remarkably high levels of many of the neurotransmitters and neuromodulators known to exist in the mammalian brain, and there are changes in multiple neurotransmitter systems in basal ganglia disorders." Located deep within the telencephalon, the basal ganglia are targets of the cerebral cortex and provide major subcortical input to the frontal regions of the brain through a relay system involving the ventral lateral nucleus(VLO.) Much of what is assumed about the purpose of the structures comes from movement disorders such as Parkinson, Ballism, and Huntington's. Hence, the traditional view, although likely limited, is that the primary function of the basal ganglia is facilitating motor control.

What is currently understood about the basal ganglia is their general organization. In order to simplify the complicated nomenclature of the basal ganglia it is useful to divide them into three components: 1) input nuclei, which have afferent connections from brain regions other than the basal ganglia, 2) output nuclei, which have efferent projections that leave the basal ganglia; and 3) intrinsic nuclei, which receive input from and project to the input and output nuclei. The input nuclei consist of the three nuclei of the striatum: the caudate nucleus, putamen, and nucleus accumbens. Information received by the input nuclei is affected by the four intrinsic nuclei: the external segment of the globus pallidus, subthalamic nucleus, substantia nigra pars compacta, and ventral tegmental area. On the output side, there are also three nuclei: the internal segment of the globus pallidus, the ventral pallidum, and the substantia nigra pars reticulata. Between the various components of the basal ganglia, lie the internal capsule, containing ascending thalamocortical fibers and descending fibers that terminate in the basal ganglia, brain stem, and spinal cord. The combination of these elements provides the basic anatomy of the basal ganglia.

The basal ganglia receive input from virtually all of the cerebral cortex but project, via a relay in the thalamus, only to portions of the frontal lobe rostral to the motor cortex. There are two prevailing views on the organization of loops in the basal ganglia. Trends in Neuroscience reported in 1990 that there is "a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature." An article written four years later for Brain Research Reviews offers a different, broader view: "interpretations of the currently available neuroanatomical and electrophysiological data on this issue have led to two opposite views that can be referred to as 'parallel processing' and information funneling' hypotheses." The first model assumes that different types of cortical information are processed through multiple, independent, parallel circuits. The informational funneling hypothesis, in contrast, suggests that information from distinct cortical areas converges at basal ganglia levels so that the information is projected back to the cortex as a complex mixture of the different input sites. Although these two models each have their advocates, recent studies have provided evidence that the processing system may be more complex than either suggests.

Four major informational inputs in the basal ganglia have been identified: motor, oculomotor, association, and limbic. The most well known of these is the motor loop. Like all structures in the basal ganglia it follows the general pattern of cortex - striatum - globus pallidus - VL0 - cortex. More specifically, the motor loop originates in an excitatory connection from either the primary motor cortex, arcuate premotor area, or the supplementary motor area which projects to the putamen of the striatum. The putamen then makes inhibitory synapses with certain intrinsic nuclei: the external segment of the globus pallidus and the substantia nigra. These nuclei, in turn, make inhibitory connections with the lateral ventricle nucleus (VLo) of the thalamus. The double negative projection releases the cells in the VLo from inhibition, boosting the activity of the SMA.

The rich diversity of neurotransmitters in the basal ganglia, including glutamate, acetylcholine, and dopamine, are instrumental in facilitating the flow of information in basal ganglia circuits. The most prominent chemical is the inhibitory amino acid GABA. An excitatory synapse facilitated by glutamate, projecting from the cerebral cortex to the striatum, begins all circuits in the basal ganglia. The GABAergic neurons of the striatum then project to the GABAergic neurons of the pallidum and substantia nigra, which in turn project out of the basal ganglia to the thalamus. The double inhibitory effect of the dual GABA projections serve to disinhibit the thalamus, providing an end result of excitatory transmission from the thalamus to the cortex facilitated by glutamate.

This basic circuit is modulated by striatal cholinergic neurons and by inputs from the substantia nigra pars compacta and the subthalamic nucleus. While neurons of the pars reticula division of the substantia nigra contain GABA, the pars compacta contains dopaminergic neurons. The substantia nigra pars compacta provides dopaminergic input to the caudate nucleus and the putamen. In Parkinson's disease, a motor disorder characterized by tremor, rigidity, and bradykinesa, the dopaminergic neurons of the pars compacta are destroyed, thus greatly reducing striatal dopamine. This deficit reduces excitation at the origin of the motor loop. Parkinson's disease is treated by replacement therapy using l-dopa, a precursor to dopamine. Dopa crosses the blood-brain barrier and boosts DA synthesis in the cells that remain alive in the pars compacta.

Another source of intrinsic input comes from the subthalamic nucleus and the external segment of the globus pallidus. The subthalamic nucleus receives input from the external segment of the globus pallidus and then projects to both segments of the globus pallidus and to the substantia nigra pars compacta. Scientists believe this excites the pallidum with a glutamatergic input, thus increasing the inhibitory effect of the pallidus on the thalamus. Lesions of the subthalamic nucleus, by breaking this loop, release the thalamus from inhibition, and result in the hyperkinetic syndrome of ballism. The disorder is characterized by uncontrollable, flinging movement of the extremities. Since the subthalamic nucleus is somatotopically organized, a partial lesion will be reflected in the corresponding part of the body.

The manifestations of ballism are an exaggerated form of the choreas that characterize Huntington's Disease, an autosomal dominant neurodegenerative disorder. Chorea, which means dance-like, is characterized by sudden, unintended movements of potentially any muscle group. While it is believed that most forms of chorea reflect a disorder of the basal ganglia, the underlying pathology is not fully understood. There is a great range in the degree with which chorea alters behavior, from a minor malfunction which can be incorporated into normal behavior to extreme motions resembling ballism. The form of chorea manifested in Huntington's is a progressive condition and what might start out as a minor abnormality in one's behavior quickly deteriorates to a life threatening condition. Moreover, the chorea in Huntington's is often marked by a writhing component, moving it closer to the phenomenom of athetosis, a slow, writhing movement.

Predominantly a disease of the striatum and the pallidum, Huntington's Disease manifests itself through atrophy and neuronal loss usually beginning near the ventricles in the medial caudate. In terms of neurotransmitter pathology, the decline in GABA is the most severe and immediate, and is followed by decreases in ACh, dopamine, and glutamate. It is believed that the disorder's gene influences the excitatory glutamate pathway so that the neurons of the striatum get overly excited and die as a result of excitotoxicity. From the striatum the disorder progresses laterally and ventrally such that the brains of people who have lived for many years with Huntington's Disease show widespread atrophy, although the neuronal cell loss remains most striking at the striatum.

Chorea is often linked with dystonia, which is both a feature as well as a name for a group of illnesses. Dystonia is generally marked by sustained muscle contractions that cause twisting and repetitive movements exhibited in abnormal involuntary postures. The types of dystonia can be classified as generalized or focal and by the patterns and syndromes they initiates. Generalized forms of dystonia usually have a childhood onset, while focal or segmental dystonias begin later in life. An example of a generalized dystonia, Torsion dystonia, (formerly known as dystonia musculorum deformans) is a rare, often familial, progressive form of dystonia. Smasmodic Toricolis (Wry neck), a form of focal dystonia, is characterized in the involuntary tendency of the patient's neck to twist to one side. A wide range of medications is used to treat dystonia: including drugs that reduce ACh, regulate GABA, act on dopamine, and serve as anticonvulsants.

Another extrapyramidal disorder of unknown pathology is Tourette Syndrome (TS). It is characterized by motor and vocal tics, which are quick involuntary movements or vocal noises such as throat clearing, sniffling, grunting, and shouting. The vocal outbursts range from noises inappropriate in their decibel to those of rude and vulgar content. Likewise, the disorder is often accompanied by emotional problems such as temper outbursts and obsessive compulsive disorder. Onset of the disorder is during childhood, and patients are often able to temporarily suppress the tics. Prior to the hyperkinetic activity, there is a feeling of tension at the site of the tic which is relieved after the execution of the tic.

The former disorders demonstrate that malfunctions of the basal ganglia can be extremely debilitating. Currently the source of knowledge on the pathology of these conditions is scarce, reflecting an ambiguous functional basis of the basal ganglia. Hopefully, further discover of the pathology of the extrapyramidal systems will lend to better diagnosis and treatment of associated disorders.

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